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Biomedical subjects

D L Morris

Publications and source records attributed to D L Morris.

At least 433 records · Page 24Linked to original sources
PubMedDate not supplied

Immunosuppression in adult female B6C3F1 mice by chronic exposure to ethanol in a liquid diet.

The overall objective of these studies was to characterize the effects of ethanol on the immunocompetence of adult female B6C3F1 mice. To obtain a significant suppression in the antibody response to SRBC, splenocytes from untreated mice had to be directly exposed to concentrations of ethanol from 0.3% to 3.0%, or to acetaldehyde at concentrations greater than 0.03%. We do not believe that these results are consistent with a role by a direct effect by either ethanol or its primary metabolite because these concentrations are higher than what could be obtained as reasonable blood levels. For in vivo exposure, we employed a pair-feeding regimen which was based on a liquid diet containing 5% ethanol (v/v) that provided 36% of the caloric intake as ethanol. Our results indicated that there was a definite temporal relationship to the consequent suppression of the antibody response to SRBC in that no effect was observed after 14 days exposure, and that the magnitude of the suppression increased from 18% after 21 days to 70% after 42 days. We also monitored the liver for histopathology and observed that the ethanol-induced liver damage was restricted to steatosis (fatty liver), which was also manifested with time and which was most pronounced after 42 days exposure. In contrast to our results with the in vivo antibody response, we saw no effect on mitogen-induced proliferation by splenocytes from ethanol-treated mice. These results prompted us to measure in vitro antibody responses by splenocytes from ethanol-treated mice. We saw no suppression of the in vitro antibody responses to SRBC, DNP-Ficoll or LPS after any length of exposure to ethanol, and speculated that the basis for the suppression of the in vivo antibody response was an indirect consequence of exposure. We subsequently determined that when normal splenocytes were cultured in 5% serum from ethanol-exposed mice (42-day group), there was a > 80% suppression relative to the serum from the pair-fed controls. As important controls for these studies, we have demonstrated that there was no difference between the responses of normal lymphocytes cultured in 5% normal mouse serum and in 5% serum taken from the pair-fed restricted controls. A determination of the ethanol content in the serum from ethanol-exposed mice (42-day group) indicated that the amount of ethanol present in these cultures was < 0.003%.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetaldehyde↗
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Serum modulation of the effects of TCDD on the in vitro antibody response and on enzyme induction in primary hepatocytes.

We have recently reported that the effects of TCDD on the in vitro antibody response can vary considerably depending on the serum conditions used in the culture media. To further investigate this phenomenon, studies were performed to compare the effects of TCDD on both splenocyte antibody responses and P450 enzyme induction (EROD) in primary hepatocytes (HPTC) derived from B6C3F1 and DBA/2 mice when evaluated in the presence of either fetal bovine serum (FBS), newborn calf serum (NBCS) or normal mouse serum (NMS). The latter studies with NMS also included crossovers where splenocytes and HPTC from B6C3F1 mice were cultured in the presence of DBA/2 serum and vice versa. Results with NBCS showed comparable suppression of antibody responses by TCDD in splenocytes from B6C3F1 and DBA/2 mice where we detected IC50 values of 3.0 and 2.8 nM, respectively. In contrast, responses in the presence of NMS showed an Ah-dependency that was characterized by a dose-related suppression of antibody responses by B6C3F1 splenocytes, but a lack of suppression in the responses by DBA/2 splenocytes. Distribution studies with radiolabelled TCDD indicated that the observed profile of activity could not be attributed to a differential uptake of the chemical into splenocytes from B6C3F1 or DBA/2 under the various serum conditions. Serum was also found to modulate the TCDD-induced EROD activity in primary HPTC and the profile of activity was identical to the effects of TCDD on in vitro antibody responses. We observed an enhanced induction of EROD in the presence of NBCS (immunosuppressive conditions) and a lower induction in the presence of FBS (non-immunosuppressive conditions), each giving the same relative magnitude of induction regardless of the mouse strain used as the source of HPTC. In contrast, induction in the presence of NMS showed an Ah-dependency and resulted in a dose-related enhancement in EROD activity in B6C3F1 HPTC but decreased activity in the DBA/2 HPTC. Cross-over studies further showed that the pattern of effects on both splenocytes and HPTC was not altered by changing the strain of mouse used as the source of serum, where each gave equivalent results. These findings demonstrate that the Ah-dependency for the effects of TCDD on both the in vitro antibody response and P450 enzyme induction are modulated by the serum environment in which the cells are exposed. The studies with NMS indicate that it is the genotype of the lymphocyte (i.e., or the HPTC), and not the strain-specific hormone environment, which confers sensitivity to TCDD.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
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Palliative therapy of malignant esophageal stricture with the bipolar tumor probe and prosthetic tube.

Patients with malignant esophageal stricture and dysphagia were prospectively randomized to receive palliative therapy with the bipolar tumor probe (17) or prosthetic tube insertion (13). Both treatments gave good relief of dysphagia compared with pretreatment values on a dysphagia score, the results being statistically significant (p less than 0.005). However, there was no difference in the improvement achieved by one method compared with the other. The tumor probe was not difficult to use and complication rates were comparable. In the Atkinson tube group, two patients developed complications related to the position of the prosthesis and in three others food blocked the tube. Treatment with the tumor probe needed repeating at intervals (median, 28 days; range, 2 to 86 days) in all but four individuals to maintain palliation, with each patient needing a median of two treatments (range, 1 to 8). The probe may have advantages in very high esophageal lesions and may facilitate the treatment of tumor overgrowth or undergrowth of a tube. The prosthetic tube may give long-lasting relief of dysphagia and remains the treatment of choice for bronchopulmonary fistulas.

Adenocarcinoma↗
PubMedDate not supplied

Artery weld strength after bipolar electrocoagulation is affected by electrolyte solutions around the artery.

We have recently shown that artery weld strength is significantly increased by increasing bipolar electrocoagulation time in fresh rabbit arteries, which had either 2 or 20 seconds of electrocoagulation under uniform conditions. In this study we investigated the effect of using either distilled water or physiologic saline around the artery during electrocoagulation in a total of 27 experiments, because it is the current practice to wash clot and liquid blood off bleeding ulcers with water. Fresh rabbit arteries were used, with a bipolar coagulation time of 2 seconds, with a constant weight of 500 gm applied to the head of the probe to standardize conditions. The bursting pressure of the coagulum was determined by cannulating the artery and increasing the pressure until the coagulum seal fractured. The artery weld strength was significantly lower when distilled water was used (median, 87.5 mm Hg; range, 10 to 225 mm Hg) compared with results when normal saline was used (median, 150 mm Hg; range, 100 to 850 mm Hg); by Mann-Whitney tests U = 42.5, Z = 2.36, and p = 0.018. These data suggest that more effective hemostasis of bleeding arteries may be achieved by not only more prolonged use of the diathermy probe, but also by using physiological saline as the washing solution instead of water, as is currently practiced.

Animals↗
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Intentional drug overdose: predictors of clinical course in the intensive care unit.

OBJECTIVE: To examine the characteristics of patients admitted to the Medical Intensive Care Unit (MICU) after intentional drug overdose. DESIGN: Retrospective chart review, descriptive. SETTING: Midwestern teaching hospital. SUBJECTS: Convenience sample of 43 patients admitted to the MICU after intentional drug overdose. OUTCOME MEASURES: Survival and disposition of those patients who survived and were discharged from the MICU. RESULTS: Ninety-five percent of the patients survived and were discharged from the MICU; Acute Physiology and Chronic Health Evaluation II scores ranged from 1 to 29 (mean, 8); Glascow Coma Scale scores ranged from 3 to 15 (mean 12.5); five patients were intubated and two patients had serious electrocardiograph changes requiring pharmacologic intervention for dysrhythmia. CONCLUSIONS: Neurologic findings were the best indicators of serious complications after drug overdose. THerefore, patients with a Glascow Coma Scale score of more than six, and who are not intubated, may not need admission to an intensive care unit.

APACHE↗
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Health effects from chronic low-level exposure to hydrogen sulfide.

The acute toxic effects of hydrogen sulfide have been known for decades. However, studies investigating the adverse health effects from chronic, low-level exposure to this chemical are limited. In this study, the authors compared symptoms of adverse health effects, reported by residents of two communities exposed mainly to chronic, low-levels of industrial sources of hydrogen sulfide, to health effects reported by residents in three reference communities in which there were no known industrial sources of hydrogen sulfide. Trained interviewers used a specially created, menu-driven computer questionnaire to conduct a multi-symptom health survey. The data-collection process and questions were essentially the same in the reference and exposed communities. The two exposed communities responded very similarly to questions about the major categories. When the authors compared responses of the exposed communities with those of the reference communities, 9 of the 12 symptom categories had iterated odds ratios greater than 3.0. The symptoms related to the central nervous system had the highest iterated odds ratio (i.e., 12.7; 95% confidence interval = 7.59, 22.09), followed by the respiratory category (odds ratio = 11.92; 95% confidence interval = 6.03, 25.72), and the blood category (odds ratio = 8.07; 95% confidence interval = 3.64, 21.18). Within the broader health categories, individual symptoms were also elevated significantly. This study, like all community-based studies, had several inherent limitations. Limitations, and the procedures the authors used to minimize their effects on the study outcomes, are discussed. The results of this study emphasize the need for further studies on the adverse health effects related to long-term, chronic exposure to hydrogen sulfide.

Adolescent↗
PubMedDate not supplied

A comparison of emergency medical services times for stroke and myocardial infarction.

OBJECTIVE: Since stroke symptoms are often vague, and acute therapies for stroke are more recently available, it has been hypothesized that stroke patients may not be treated with the same urgency as myocardial infarction (MI) patients by emergency medical services (EMS). To examine this hypothesis, EMS transport times were examined for both stroke and MI patients who used a paramedic-level, county-based EMS system for transportation to a single hospital during 1999. METHODS: Patients were first identified by their hospital discharge diagnosis as stroke (ICD-9 430-436, n = 50) or MI (ICD-9 410, n = 55). Trip sheets with corresponding transport times were retrospectively obtained from the 911 center. A separate analysis was performed on patients identified by dispatchers with a chief complaint of stroke (n = 85) or MI (n = 372). RESULTS: Comparing stroke and MI patients identified by ICD-9 codes, mean EMS transport times in minutes did not meaningfully differ with respect to dispatch to scene arrival time (8.3 vs 8.9, p = 0.61), scene time (19.5 vs 21.4, p = 0.23), and transport time (13.7 vs 16.2, p = 0.10). Mean total call times in minutes from dispatch to hospital arrival were similar between stroke and MI patients (41.5 vs 46.4, p = 0.22). Results were similar when comparing patients identified by dispatchers with a chief complaint indicative of stroke or MI. CONCLUSION: In this single county, EMS response times were not different between stroke and MI patients. Replication in other EMS settings is needed to confirm these findings.

Efficiency, Organizational↗
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Biliary pharmacokinetics of sulbactam plus ampicillin in humans.

The biliary pharmacokinetics of sulbactam and ampicillin was investigated in 19 patients with normal liver function who were undergoing surgery of the biliary tract. The combination of sulbactam (0.5 g) plus ampicillin (1 g) was given intravenously to five patients with T-tube drainage of the common bile duct. Mean peak concentrations of sulbactam (19.4 micrograms/ml) and ampicillin (471 micrograms/ml) in the bile occurred 0.5-1 hr after administration. Biliary excretion was estimated to account for approximately 0.24% of the sulbactam dose and 2.8% of the ampicillin dose. Fourteen other patients received the same dose of sulbactam/ampicillin immediately before elective cholecystectomy. Respective mean concentrations of sulbactam and ampicillin at the time of gallbladder removal were 4.3 micrograms/ml and 15.9 micrograms/ml in gallbladder bile and 6.3 micrograms/g and 7.7 micrograms/g in gallbladder wall tissue. These results, together with the antibacterial spectrum and potency of the combination, suggest that sulbactam/ampicillin is suitable for prophylactic use in biliary tract surgery.

Ampicillin↗
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A randomized comparative study of sulbactam plus ampicillin vs. metronidazole plus cefotaxime in the management of acute appendicitis in children.

Sulbactam is a beta-lactamase inhibitor that, when combined with ampicillin, gives the latter antibiotic a broad spectrum of activity, making it suitable for use as a prophylactic agent in acute appendicitis. In a single-blind, randomized trial, the efficacy of sulbactam plus ampicillin was compared with that of metronidazole plus cefotaxime. Thirty-five children undergoing appendectomy received intravenous sulbactam and ampicillin, while 38 children received metronidazole and cefotaxime. Single doses were given unless the appendix was considered gangrenous or perforated, in which case the drugs were administered for 72 hr. There were three wound infections in the group given sulbactam and ampicillin and five in the group given metronidazole and cefotaxime. The combination of sulbactam and ampicillin was well tolerated and appeared to be at least as effective as that of metronidazole and cefotaxime in the prevention of sepsis following appendectomy.

Acute Disease↗
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Is grasping impaired in hemispatial neglect?

Patients with right unilateral cerebral stroke, four of which showed acute hemispatial neglect, and healthy aged-matched controls were tested for their ability to grasp objects located in either right or left space at near or far distances. Reaches were performed either in free vision or without visual feedback from the hand or target object. It was found that the patient group showed normal grasp kinematics with respect to maximum grip aperture, grip orientation, and the time taken to reach the maximum grip aperture. Analysis of hand path curvature showed that control subjects produced straighter right hand reaches when vision was available compared to when it was not. The right hemisphere lesioned patients, however, showed similar levels of curvature in each of these conditions. No behavioural differences, though, could be found between right hemisphere lesioned patients with or without hemispatial neglect on either grasp parameters, path deviation or temporal kinematics.

Aged↗
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Exploration of the transformation potential of a unique male rat protein alpha2u-globulin using hamster embryonic cells.

Several environmentally and socially important chemicals such as d-limonene and unleaded gasoline have been demonstrated to induce alpha2u-globulin (alpha 2u) nephropathy in male rats. Substantial progress has been made in characterizing the biological effects of these chemicals on the kidney and in further defining prerequisite events in the pathogenesis of this syndrome. The alpha 2u increase in the kidney is hypothesized to be the proximal event in the toxicologic and tumorigenic sequelae associated with administration of these xenobiotics over the male rat's lifetime rather than a direct effect of the administered chemical. The administered chemical appears to simply mediate the increase in alpha 2u concentration in the kidney. To further investigate the properties of alpha 2u, this protein was tested in the pH 6.7 Syrian hamster embryo (SHE) cell transformation assay. The alpha 2u caused morphological transformation in these cells, whereas another protein, bovine serum albumin, did not induce transformation at equimolar concentrations, suggesting a protein-specific phenomenon. Neither d-limonene nor trimethylpentane (a causal component in unleaded gasoline) induced SHE cell transformation. These results support the hypothesis that alpha 2u increase in proximal convoluted tubules may directly cause renal tumorigenesis in male rats. The SHE cell transformation assay may be a useful tool for mechanistic studies of this syndrome.

Alpha-Globulins↗
PubMedDate not supplied

Phenobarbital does not promote hepatic tumorigenesis in a twenty-six-week bioassay in p53 heterozygous mice.

The tumorigenic potential of phenobarbital was examined in a 26-wk carcinogenesis bioassay using p53 heterozygous mice and wild-type controls. Fifteen mice/sex/genotype were exposed to either 500 or 1,000 ppm phenobarbital in the diet. Dietary administration of 3,750 ppm p-cresidine, a transspecies mutagenic carcinogen, to both heterozygous and wild-type mice served as a positive control. Phenobarbital treatment caused increases in liver:body weight ratios and histologic evidence of centrilobular hepatocellular hypertrophy. No tumors were observed in any phenobarbital-treated mice. Mice given p-cresidine exhibited a moderate reduction in body weight gain over the course of the study. Heterozygous mice treated with p-cresidine exhibited a high incidence of urinary bladder tumors. Similar tumors were also present in a small number of p-cresidine-treated wild-type mice. Our results demonstrate the lack of a hepatic tumor response to phenobarbital, a compound that is a potent and potent and prototypic hepatic microsomal enzyme inducer, a nongenotoxic rodent carcinogen, and a human noncarcinogen. This finding supports the continued utility of this model as an alternative to the mouse bioassay for human carcinogenic safety assessment of potentially genotoxic carcinogenes because it did not produce a false-positive response to this potent nongenotoxic agent.

Aniline Compounds↗
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Interspecies differences in renal localization of cyclooxygenase isoforms: implications in nonsteroidal antiinflammatory drug-related nephrotoxicity.

Cyclooxygenase (COX) exists in 2 related but unique isoforms: one is constitutive (COX-1) and functions in normal cell physiology, and the other is inducible (COX-2) and is expressed in response to inflammatory stimuli. Nonsteroidal antiinflammatory drugs (NSAIDs) cause renal toxicity following inhibition of renal cyclooxygenases. Humans and animals exhibit differences in susceptibility to NSAID-related renal toxicity, which may be associated with differences in expression of 1 or both isoforms of COX in the kidney. In this study, we evaluated COX-1 and COX-2 expression in the kidneys of mixed-breed dogs, Sprague-Dawley rats, cynomolgus monkeys, and humans. In addition, the effect of volume depletion on renal COX expression was investigated in rats, dogs, and monkeys. COX expression was evaluated using 1 or more of the following procedures: reverse transcriptase polymerase chain reaction, in situ hybridization, and immunohistochemistry. We demonstrated that both COX isoforms are expressed in the kidneys of all species examined, with differences in the localization and level of basal expression. COX-1 is expressed at high levels in the collecting ducts and renal vasculature of all species and in a small number of papillary interstitial cells in rats, monkeys, and humans. Basal levels of COX-2 are present in the maculae densa, thick ascending limbs, and papillary interstitial cells in rats and dogs and in glomerular podocytes and small blood vessels in monkeys and humans. COX-2 expression is markedly increased in volume-depleted rats and dogs but not monkeys. These results indicate that significant interspecies differences exist in the presence and distribution of COX isoforms, which may help explain the difference in species susceptibility to NSAID-related renal toxicity.

Adult↗
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The pathologist and toxicologist in pharmaceutical product discovery.

Significant change is occurring in the drug discovery paradigm; many companies are utilizing dedicated groups from the toxicology/ pathology disciplines to support early stage activities. The goal is to improve the efficiency of the discovery process for selecting a successful clinical candidate. Toxicity can be predicted by leveraging molecular techniques via rapid high-throughput, low-resource in vitro and in vivo test systems. Several important activities help create a platform to support rapid development of a new molecular entity. The proceedings of this symposium provide excellent examples of these applied concepts in pharmaceutical research and development. Leading biopharmaceutical companies recognize that a competitive advantage can be maintained via rapid characterization of animal models, the cellular identification of therapeutic targets, and improved sensitivity of efficacy assessment. The participation of the molecular pathologist in this quest is evolving rapidly, as evidenced by the growing number of pathologists that interact with drug discovery organizations.

Animals↗
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Revolution through genomics in investigative and discovery toxicology.

The remarkable technologic and methodologic advances spurred on by the Human Genome Project are being applied throughout the life sciences. In the field of toxicology, high-resolution assays now make it possible to discover virtually all the differences in gene expression brought on by exposure to a particular xenobiotic. There are 2 principal approaches used to build a catalog of changes in gene expression: hybridization microarrays and gel-based methods, such as differential display and AFLP-based mRNA finger-printing. The power of such approaches is exemplified by the identification of more than 300 genes that differ in expression level by at least 2-fold in response to the nongenotoxic rodent liver carcinogen phenobarbital.

Animals↗
PubMedDate not supplied

The health effects of living near cement kilns; a symptom survey in Midlothian, Texas.

Cement kilns are major sources of toxic air emissions. Regulations based on demonstrated concentrations of specific chemicals, and risk assessments with inherent limitations and uncertainties, are the current methods of preventing exposure to 'unsafe' emission levels. Monitoring data are frequently incomplete. These limitations mandate that residents residing near cement kilns be evaluated for adverse health effects. This study reports findings from a symptom survey conducted in Midlothian, Texas, which adds to the limited but growing body of knowledge showing that persons living near cement kilns are experiencing increased respiratory effects. This cross-sectional study uses randomized sampling and an extensive health questionnaire, covering 12 physiological systems, to determine differences in reported health symptoms between the study community (Midlothian, Texas, n = 58) and the reference community (Waxahachie, Texas, n = 54). Findings indicate significant elevations in reported respiratory symptoms in the study community (p-value 0.002). Although the comparatively small sample size is a limitation, the fact that only 'respiratory effects' were highly significant supports the efficacy of this investigation. Respiratory effects would be the major anticipated outcome from the known exposures under investigation. This specificity of response (i.e., elevation in respiratory symptoms only), indicates that 'response bias' was not a significant factor in this study.

Adolescent↗